Desensitization: achieving immune detente

Abstract

Antibodies to donor HLA (human leukocyte antigen) and/or ABO antigens were a contraindication to transplantation of most organs for decades. Desensitization protocols have shown the ability to produce reduction of such antibodies sufficient to achieve a successful transplantation. The two major protocols in use are high-dose IVIg or plasmapheresis with low-dose IVIg. The protocols differ in the basic treatment and, to some degree, in their application, but both use standard immunosuppressive agents as well as more recently developed adjunctive agents such as cell-depleting antibodies. Graft and patient survival with both types of protocol are comparable to that of non-sensitized patients, although desensitized patients do have a higher incidence of antibody-mediated rejection (AMR). Antibodies to donor antigens may persist after transplantation, and while the initial antibody titer represents the level of difficulty for successful desensitization, the strength of antibodies that persist after transplantation reflects the risk of AMR. Current protocols do not eliminate B cell clones specific for donor HLA; therefore, desensitized patients remain at an increased risk of antibody rebound if patients experience pro-inflammatory events. Therefore, ongoing antibody monitoring is crucial for early detection of antibody-mediated graft injury. Importantly, the results of numerous programs show that ABOi- and HLA-positive crossmatch renal transplantation, with proper desensitization, can be performed successfully. Further, in addition to increasing the rate of transplantation among sensitized patients, desensitization is providing insight into immunoregulatory processes and may provide information useful in diseases involving immune dysfunction.

Effect of infusion of monoclonal antibodies to tumour necrosis factor‐receptor super family 25 on graft rejection in allo‐immune mice receiving autologous marrow transplantation

“…In the renal transplant field it has been estimated that up to 30% of individuals on the transplant waiting list express significant titres of such antibodies (through previous transfusion, failed grafts or pregnancy), and additional data indicate that such titres are generally associated with an increased risk of antibody‐mediated rejection and poor graft survival . It has long been recognized that it is important to develop techniques that can obviate the clear disadvantages to graft survival associated with such pre‐sensitization . Both alloantibodies per se, and anti‐donor reactive B cells, capable of acting as antigen‐presenting cells or producing pathological cytokines, are thought to be causally implicated in enhanced rejection in sensitized individuals, though it should be noted that there is also some thought that regulatory B (Breg) cells may in turn counter the adverse effect of sensitized B cells …”

“…15 It has long been recognized that it is important to develop techniques that can obviate the clear disadvantages to graft survival associated with such pre-sensitization. 16 Both alloantibodies per se, and anti-donor reactive B cells, capable of acting as antigen-presenting cells 17 or producing pathological cytokines, are thought to be causally implicated in enhanced rejection in sensitized individuals, though it should be noted that there is also some thought that regulatory B (Breg) cells may in turn counter the adverse effect of sensitized B cells. 18 Current protocols have investigated mechanisms for desensitization of immune hosts, with the aim of facilitating engraftment to such recipients, using plasmapheresis, B-cell-depleting (anti-CD20) antibodies and intravenous immunoglobulin.…”

Methodological aspects of anti-human leukocyte antigen antibody analysis in solid organ transplantation

“…Numerous reports have demonstrated that changing CDC-CM from positive to negative via durable DSA removal significantly reduces the risk of graft loss. The short-term graft survival in such recipients is not significantly different from recipients without CDC-positive DSA [69][70][71][72][73][74][75] .…”

“…The main reasons for high background levels may be related to antibodies reacting to latex, autoimmune disease(s), and some medications (IVIG) [75,[115][116][117] . Non-specific antibody binding complicates antibody analysis due to the appearance of multiple false positive antibodies and may affect organ allocation and the interpretation of VCM [118] .…”

The immune-modulator AS101 reduces anti-HLA antibodies in sera of sensitized patients: A structural approach

“…Presence of donor specific anti HLA antibodies in the serum of prospective transplant recipients is one of the major causes for transplant delay and of poor transplant outcome and therefore great effort has been devoted to finding ways to overcome this immunologic barrier [23][24][25]. Leading strategies implemented for overcoming the anti-HLA Ab barrier include logistic solutions such as donor exchange and unique allocation systems [26] or therapeutic methods of desensitization, many of which include utilization of IVIg as well as other immune-modulators [27,28].…”